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Abstract
A large body of evidence has implicated Abeta peptides and other derivatives of the
amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease
(AD). However, the functional relationship of APP and its proteolytic derivatives
to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates
the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress
APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons
that overexpress APP, as well as nearby neurons that do not. This depression depends
on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic
depression from excessive Abeta could contribute to cognitive decline during early
AD. In addition, we propose that activity-dependent modulation of endogenous Abeta
production may normally participate in a negative feedback that could keep neuronal
hyperactivity in check. Disruption of this feedback system could contribute to disease
progression in AD.